Docking on Lipid II—A Widespread Mechanism for Potent Bactericidal Activities of Antibiotic Peptides

• Published in: Journal of molecular biology 2019-08, Vol.431 (18), p.3520-3530
• Main Authors: Grein, Fabian, Schneider, Tanja, Sahl, Hans-Georg
• Format: Article
• Language: English
• Subjects: antibiotics; cell wall biosynthesis; defensins; lipid II; peptidoglycan
• ISSN: 0022-2836; 1089-8638
• DOI: 10.1016/j.jmb.2019.05.014

Natural product antibiotics usually target the major biosynthetic pathways of bacterial cells and the search for new targets outside these pathways has proven very difficult. Cell wall biosynthesis maybe the most prominent antibiotic target, and ß-lactams are among the clinically most relevant antibiotics. Among cell wall biosynthesis inhibitors, glycopeptide antibiotics are a second group of important drugs, which bind to the peptidoglycan building block lipid II and prevent the incorporation of the monomeric unit into polymeric cell wall. However, lipid II acts as a docking molecule for many more naturally occurring antibiotics from diverse chemical classes and likely is the most targeted molecule in antibacterial mechanisms. We summarize current knowledge on lipid II binding antibiotics and explain, on the levels of mechanisms and resistance development, why lipid II is such a prominent target, and thus provide insights for the design of new antibiotic drugs. [Display omitted] •Lipid II acts as a docking molecule for many antibiotics from diverse chemical classes.•Lipid II binders include (lipo-)glycopeptides, depsipeptides, lantibiotics, defensins and bacteriocins.•Lipid II clearly appears to be much more than a mere PGN building block.•Cellular effects of interfering with Lipid II are complex and apparently trigger irreversible physical damage to the cells.